Diclofenac (2-(2-[2,6-dichlorophenylamino]phenyl)acetic acid) is one of the most widely used non-steroidal anti-inflammatory drugs due to its marked pharmacological activity.
A number of formulations of diclofenac for parenteral administration are known, wherein it is present, for example, as a sodium, potassium, diethylamine or 2-hydroxyethylpyrrolidine salt.
Parenteral formulations of diclofenac, in particular of its sodium salt, are disclosed, for example, in U.S. Pat. No. 4,711,906.
Thiocolchicoside, also known as 3-demethyl-thiocolchicine glucoside, is a glucoside extracted from the seeds of Colchicum autumnale, which possesses a muscle-relaxant, anti-inflammatory, analgesic and anaesthetic action. It is frequently administered in combination with other medicaments, such as anti-inflammatories.
Patent application PCT/TR2009/000137 discloses pharmaceutical compositions containing thiocolchicoside and a non-steroidal anti-inflammatory drug. The compositions can take the form of an aqueous or non-aqueous solution suitable for intravenous, intramuscular or subcutaneous injection.
Pharmaceutical compositions in solid form containing a diclofenac salt and thiocolchicoside are disclosed in EP 0837684A1 (equivalent to FR2735369).
Patent application PCT/EP2012/061468 discloses a patch for transdermal release, containing diclofenac or a pharmaceutically acceptable salt thereof and thiocolchicoside.
WO2012/053012 discloses a topical composition in the form of a nanoemulsion comprising diclofenac sodium salt and thiocolchicoside.
Pharmaceutical compositions containing 25 or 75 mg of diclofenac sodium salt and 2 or 4 mg of thiocolchicoside in the form of an injectable solution are described in Minerva Anestesiologica, October 1991, pages 1084-1085 and in Bollettino Chimico Farmaceutico 1993, 132/6, pages 203-209. They are a combination of two separate preparations of diclofenac and thiocolchicoside useful for extemporaneous administration. Said extemporaneous injectable solutions are not proprietary medicaments properly so called, as in practice they are prepared at the time of use, and consequently lack long-term stability data.
The availability of a novel association between diclofenac and thiocolchicoside simultaneously present in a pharmaceutical form which presents as a stable injectable preparation in the terms required by the health authorities is therefore of great interest.
The prior art demonstrates that diclofenac is a substance which is relatively unstable in solution, and that the liquid formulations of said substance therefore require the presence of a stabilising agent. The above-mentioned U.S. Pat. No. 4,711,906 discloses stable aqueous solutions of diclofenac containing a mixture of propylene glycol and polyethylene glycol. The chemical stability of said solutions is obtained by adding a reducing agent which can be a sulphite, such as sodium bisulphite, cysteine and/or cysteine hydrochloride, acetylcysteine and/or acetylcysteine hydrochloride, or a thiosulphate. Their chemical stability is further improved by the presence of lidocaine in addition to the reducing agent.
When preparing a liquid composition containing diclofenac and thiocolchicoside, the inventors of the present application have found that it is necessary to overcome a number of technological difficulties, the most important requirement being to prevent the degradation of one or both of the active ingredients when formulated in a single unit dose solution.
The antioxidant most widely used to stabilise diclofenac in liquid solutions is sodium bisulphite. There are numerous formulations on the market containing this antioxidant. Other antioxidants used are cysteine, acetylcysteine and reduced glutathione.
Thiocolchicoside also presents stability problems in solution. The chemical and physical compatibility of thiocolchicoside with other injectable medicaments frequently combined with it, including anti-inflammatories, is described in Farmaco, 2002, 57(11), 925-930.
The authors of the present invention have found that the addition of thiocolchicoside to a formulation containing diclofenac makes the use of the above-mentioned antioxidants problematic, if not impossible, as their presence in the solution causes significant degradation of thiocolchicoside and diclofenac under ambient and supra-ambient storage conditions (40° C.). As the number of antioxidants suitable for parenteral/injectable use is limited, the impossibility of using said stabilizing agents makes it very complex to obtain formulations which are potentially stable under the conditions required by the health authorities when the product is registered.
Tert-butyl-4-hydroxyanisole, also known as butylated hydroxyanisole or BHA, is an antioxidant widely used in the food and pharmaceutical industry. It is used in fats and oils, foods containing fats, essential oils, and food packaging materials. BHA is a mixture of two isomers: 2-tert-butyl-4-hydroxyanisole (2-BHA) and 3-tert-butyl-4-hydroxyanisole (3-BHA). The two BHA isomers are phenols and therefore react rapidly with free radicals, thus protecting the foods to which they are added against oxidation and alteration of their organoleptic characteristics (colour, odour, flavour and texture).